The interest in Poly ADP ribose polymerase (PARP) inhibitors is increasing in accordance with the detection of a high rate of BRCA1 or BRCA2 gene mutation due to the recent genetic breast and ovarian cancer. In general, with BRCA genetic mutations the breast cancer risk is 5 times higher, and one of them in particular, the probability of a considerable risk for TNBC (Triple-negative breast cancer) is increasing. TNBC accounted for 15% of breast cancer patients is related to the lacks of estrogen receptors, progesterone receptors. As there has been no special treatment until now, the target of TNBC contains significant market potential.
The PARP is the one of repairing enzyme for damaged single-stranded DNA breakes. In case of inhibition of PARP, the damage of single strand consecutively generates defects in double-stranded DNA. At this point, the defects of double strand can be recovered by BRCA protein complex. Thus in general, even though the one of the DNA repairing paths is not working, most of cell can be alive. But the cancer patients who inheritantly lost repairing path of BRCA protein complex by the mutation of BRCA1/BRCA2 can increase dependancy on the PARP pathway of DNA repairing. Especially, as the possibility of defects in DNA replication in case of cancer cell is higher than normal cell, the cancer cell has higher dependance on PARP path than normal cell. In other words, the PARP inhibitors fundamentally block the repairing system of cancer cell following apoptosis of cancer cell.
To date, 18 members of the PARP family have been identified and characterized, with PARP-1 being the most thoroughly studied and PARP-2 being its closest relative. Despite the large number of enzymes in this family, PARP-1 accounts for >90% of the ADP-ribosylation within the cell. Because of the structural homology between PARP-1 and PARP-2, most PARP-1 inhibitors also inhibit PARP-2. The PARP-1 enzyme is a 113 kDa protein with three major structural domains, a DNA binding domain with two zinc fingers, a 55 kDa catalytic domain, which utilizes nicotinamide adenine dinucleotide (NAD+) as a substrate to construct polymers of ADP-ribose on histones and other nuclear acceptor proteins including the automodification domain of PARP-1 itself. It is published and generally accepted that the catalytic activity of PARP-1 is stimulated by DNA damage caused by peroxidation, irradiation, and DNA-damaging chemicals, chemotherapeutic agents. Toward this end, PARP-1 enzyme binds to damaged DNA and stimulates polymerization of ADP-ribose resulting in the unwinding of DNA from histones and exposing the damaged DNA for repairing. Accordingly, PARP-1 is associated with DNA repairing and maintenance.
TNBC breast cancer is associated with BRCA1 and BRCA2 gene mutations. The central role of the BRCA gene is the recovery of double stranded brake (DSB) through homologous recombination (HR). PARP-1 inhibition will lead to an increase in single strand breaks (SSB), the preponderance of these SSBs will eventually lead to increased DSBs. The increase of DSBs in BRCA1/BRCA2 gene mutation cancer patients in the presence of HR deficient cell types leads to chromosomal aberrations and instability of the genome resulting in cell death.
A conventionally known PARP inhibitor Olaparib (WO2002036576, WO2003093261, US2004876080, US2005059663) are developed for the treatment of cancer, such as, specifically, stomach cancer, ovarian cancer, breast cancer.
Following four patents are published with modified phenyl group of phthalazinone structure (WO2007138351, WO2007138355, WO2009063244, and WO2009112832).
Since 2011 pharmaceutical companies from China and India published various patent with modified derivates of Olaparib (WO2012019426A1, WO2012019427A1, WO2012019430A1, WO2012071684A1, WO2012072033A1 and WO2012014221).
As anticancer agents PARP inhibitors, has been progressed with respect to the prior published clinical literature, has a new mechanism of action for the treatment of cancer. PARP inhibitors are development as first target for personalized medicine based on personal genetic mutation so that worldwide attention is focused. PARP inhibitors have been reported to exhibit in particular a significant effect on cancer caused by genetic mutations in BRCA1/2, and the present invention with new mechanism for the treatment of cancer patients with genetic variation in BRCA1/2 genes is expected to open a new chapter.